Moisture-activatable adhesives for medical application purposes

ABSTRACT

An adhesive for medical patches or for transdermal therapeutic systems which contains a component or a combination of at least two components, such as (a) polyvinyl alcohols, (b) cellulose derivatives, (c) polyethers, (d) acid anhydrides and their acids and salts, as well as (e) non-pressure-sensitive adhesive polyacrylates. The adhesive has a tackiness which is activated and/or increased by contact with moisture or by absorption of moisture.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application of InternationalApplication No. PCT/EP03/012117, filed on Oct. 31, 2003, which claimspriority of German application number 102 52 725.3, filed on Nov. 13,2002.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to moisture-activatable adhesives formedical application purposes. More particularly, the present inventionrelates to medical patches and transdermal therapeutic systems. Theinvention further comprises medical patches and transdermal therapeuticsystems containing such moisture-activatable adhesives.

2. Description of the Prior Art

Medical patches and transdermal therapeutic systems (TTSs) generallypossess a pressure-sensitive adhesive layer which enables self-adhesiveattachment to the skin. In the case of transdermal therapeutic systems,the pressure-sensitive adhesive layer often also serves as an activesubstance reservoir, i.e. the pressure-sensitive adhesive contains oneor more active substances which are delivered to the skin during theperiod of application.

In many cases, the pressure-sensitive adhesive layers of medical patchesor of TTSs are made of polymers such as polyacrylates, polyisobutylenes,polyisoprenes or the like. A disadvantage of such pressure-sensitiveadhesives, however, is that they adhere only poorly on a moist support.For this reason, when a patch or TTS is applied to a moist skin site theadhesion between the pressure-sensitive adhesive matrix layer of thepatch or TTS and the skin may be insufficient. This problem exists inparticular with patients who perspire vigorously, or with parts of theskin that show increased transpiration. Due to the insufficientadhesion, the patch or TTS may become detached entirely or partially sothat the intended function can no longer be fulfilled. This mayparticularly affect the delivery of active substances from TTSs.

Because of the pressure-sensitive adhesive properties, that layer of apatch or TTS which is to be adhered to the skin has to be covered with adetachable protective film. Furthermore, some of the conventionalpressure-sensitive adhesive compounds utilised for patches or TTSs havea strong tendency towards showing “cold flow”, which may lead to theadhesive compound emerging from the patch or TTS during storage, andsubsequently causing the patch or TTS to stick to its pack. In addition,the conventional pressure-sensitive adhesive compounds aredisadvantageous in that they are prepared almost exclusively withorganic solvents, which may lead to problems due to the residual solventcontent.

Furthermore, with active substance-containing adhesive matrix layers, itmust be taken into account that at least for some active substances oractive substance types an excessively lipophile environment can have anegative effect on the release of the active substances from the matrix.As a consequence, it is no longer possible to achieve the intendedactive substance release rate.

SUMMARY OF THE INVENTION

An object of the present invention is to provide an adhesive for medicalpatches or TTSs which does not have the aforementioned disadvantages,and which possesses improved adhesive properties, in particular on amoist support.

This and other objects are achieved according to the description tofollow and from the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, the adhesive for medical patches ortransdermal therapeutic systems contains a component or a combination ofat least two components from the group comprising (a) polyvinylalcohols, (b) cellulose derivatives, (c) polyethers, (d) acid anhydridesand their acids and salts, as well as (e) non-pressure-sensitiveadhesive polyacrylates.

It is of essential importance that the tackiness of the adhesivesaccording to the invention is activated and/or increased by contact withmoisture or by absorption of moisture. This particularly means that theadhesive layer produced from an adhesive according to the inventioneither (i) initially has no self-adhesive properties and only becomestacky after being moistened or upon contact with a moist support (e.g. amoist skin site), or (ii) that an adhesive layer according to theinvention is per se already pressure-sensitive adhesive but its adhesiveeffect is increased by absorption of moisture. In this manner, areliable adhesive effect on moist or perspiring skin is ensured. In thecontext of the present invention, the term “moisture-activatable” meansboth that the tackiness may be initiated by the action of moisture, andthat an existing pressure-sensitive adhesive property may be increasedunder the influence of moisture.

By utilizing the principle of moisture activatability it is possible toprepare adhesive layers which are non-adhesive or only slightly adhesivein dry condition (e.g. during storage), so that it is not necessary tocover this adhesive layer with a detachable protective film. Since theadhesive layers according to the invention are non-adhesive or onlyslightly adhesive in dry condition, they are not prone to “cold flow”,which is a further advantage since the patches, TTSs etc. are therebyprevented from sticking to the package.

The property of the adhesive effect being activated or increased byabsorption of moisture is essentially due to the formulation accordingto the invention of the composition of the adhesive, i.e. by a contentof certain components or polymers according to the present invention. Inthis context it is additionally advantageous that in most caseshydrophile polymers, such as polyvinyl alcohols or cellulosederivatives, are used. A further advantage results from the fact that inmany cases the adhesive masses can be prepared on the basis of water orusing aqueous solvent mixtures, so that organic solvents can largely ortotally be dispensed with. It is thereby possible to save complexexaminations to determine the residual solvent content, possible skinirritating effects caused by solvents are avoided, and the costs forwaste air disposal incurred in the production are reduced.

Finally, according to the invention, provision is also made forincreasing the hydrophile character of the adhesives, and thereby of thelayers of adhesive prepared therefrom, by adding further hydrophilepolymers or hydrophile auxiliary substances. The adhesives according tothe invention, and thereby the TTSs prepared therefrom, are thereforeespecially suitable for transdermal administration of active substanceswhere a hydrophile environment, i.e. a hydrophile character of theactive substance-containing adhesive matrix, has a positive effect onthe release behaviour of the TTS.

The adhesive compositions according to one embodiment of the inventioncontain a combination of at least two components, selected from thegroup comprising (a) polyvinyl alcohols, (b) cellulose derivatives, (c)polyethers, (d) acid anhydrides and their acids and salts, as well as(e) non-pressure-sensitive adhesive polyacrylates, at least two of thesecomponents being selected from different classes (a) to (e). Such acombination may, for example, contain a polyvinyl alcohol (a) and apolyether (c).

Components suitable for the inventive, moisture-activatable adhesivecomposition are cellulose derivatives (b), especially cellulosederivatives from the group comprising hydroxypropyl methyl cellulose,hydroxypropyl cellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose and hydroxypropyl ethyl cellulose.

In accordance with further embodiments of the present invention, themoisture-activatable adhesives contain one or more polymers from theclass of the polyethers (c), such as from the class of the polyvinylalkyl ethers. The alkyl groups are alkyl groups with 1 to 20 C atoms;suitable are straight-chain, branched-chain and cyclic alkyl residues,especially polyvinyl methyl ethers, polyvinyl ethyl ethers, polyvinylisobutyl ethers and polyvinyl cyclohexyl ethers.

Furthermore, copolymers of the mentioned polyvinyl ethers with othermonomers, especially copolymers with carboxylic acid anhydrides, may beused to advantage as well.

Acid anhydride group-containing polymers, such as maleic acidanhydride-containing copolymers, are used as acid anhydrides (componentd), for example copolymers of methyl vinyl ether and maleic acidanhydride. Such copolymers are available under the name of GANTREZ (fromISP), for example; Gantrez AN types (anhydride) are used withpreference.

Apart from the above, salts or the acid forms of the indicated acidanhydrides may also be used to advantage, such as Gantrez S types (acidforms of AN types, e.g. Gantrez S 97 BF, cf. Example 3), for example.

Furthermore, maleic acid anhydride and other carboxylic acid anhydridesare also suitable as acid anhydrides.

It has furthermore proved advantageous to add non-pressure-sensitiveadhesive polyacrylates, especially film-forming polyacrylates, such asEUDRAGIT® 40 D (Röhm), to the inventive adhesives as the component (e);by adding such film-forming, non-pressure-sensitive adhesive polymers itis possible to increase the duration of adhesion, and the adhesivebehaviour may be influenced favourably. Further suitable film-formingpolyacrylates are in principle known to those skilled in the art.

The proportion of the non-pressure-sensitive adhesive polymers, relativeto the sum of the polymer components of the adhesive compound, can bevaried within a wide range in order to adjust the desired adhesiveproperties; thus, the polyacrylate portion in such a formulation mayamount to 25-95%-wt., such as 50-80%-wt., for example.

According to a one embodiment of the present invention, the adhesivecontains at least one film-forming polymer from the group of thepolyacrylates and at least one polymethyl vinyl ether-polymaleic acidanhydride copolymer (cf. Example 2).

The invention furthermore comprises moisture-activatable adhesivecompositions with a content of polyvinyl alcohol (a). According to oneembodiment of the present invention, the adhesive formulation containspolyvinyl alcohol(s) and at least one polymethyl vinyl ether-polymaleicacid anhydride copolymer, the portion of polyvinyl alcohol being1-80%-wt., such as 5-55%-wt., relative to the sum of these two polymercomponents.

The components (a) polyvinyl alcohols, (b) cellulose derivatives, (c)polyethers, (d) acid anhydrides and their acids and salts and (e)non-pressure-sensitive polyacrylates are per se moisture-activatable incorrespondence with their respective type, i.e. they become tacky afterbeing moistened, or they are not tacky per se. For example, thecomponents (a) (polyvinyl alcohols) and (b) (cellulose derivatives) are,according to their type, moisture-activatable and tacky per se, andtheir degree of tackiness may vary depending on the type.

This correspondingly applies to a copolymer of polyether (component (c))and acid anhydride (component (d)), such as Gantrez AN-139 BF, as wellas to acid-type Gantrez S-97 BF.

Where the adhesive contains a component (selected from components (a) to(e)) that is not per se tacky or moisture-activatable, this adhesiveshould additionally contain a portion of at least 5.0%-wt., or even atleast 10.0% -wt., of a tacky, moisture-activatable component (selectedfrom the components (a) to (e)).

If, for example, an adhesive according to the invention contains acombination of polyvinyl alcohol (component (a)) with a copolymer ofpolyether (component (c)) and acid anhydride (component (d)), and a typeof polyvinyl alcohol is used that possesses practically nomoisture-activatability as adhesive (e.g. MOWIOL® 28-99; cf. Example 1),the portion of the copolymer (sum of the components (c) and (d)) shouldamount to 5.0%-wt.

If, for example a combination of a copolymer of polyether (component(c)) and acid anhydride (component (d)), e.g. Gantrez AN 169 BF, withnon-pressure-sensitive adhesive polyacrylates (component (e); e.g.EUDRAGIT® 4 NE 40 D) is used for an adhesive according to the invention,the portion of the copolymer (sum of the components (c) and (d)) shouldcontain at least 10.0%-wt.

It may furthermore prove advantageous for adjusting the desired adhesiveproperties to admix further polymer components to themoisture-activatable adhesives according to the invention, such aspolymers from the group comprising polyvinyl pyrrolidones, gelatine,starch and starch derivatives. Apart from that, a large number offurther components is in principle suitable for the manufacture of themoisture-activatable adhesive substances, provided that they haveproperties that are similar to those of the polymers mentioned herein.

The invention furthermore provides that auxiliary substances oradditives are added to the adhesive compositions, respectively theadhesive layers. Suitable for this purpose are in particular fillers(e.g. SiO₂), colourants (e.g. TiO₂), thickeners or viscosity-enhancingadditives (e.g. aerosil), emulsifiers (e.g. polyethoxylated sorbitanfatty acid esters such as TWEEN® or polyethoxylated fatty alcohols suchas BRIJ®), plasticizers (e.g. polyethylene glycol, glycerol), sweeteners(e.g. sorbitol, aspartame, saccharin), flavourings, preservatives (e.g.sorbic acid and its salts) and dehydrating agents (e.g. sodium sulfate).

Organic acids, particularly from the groups of the saturated alkanoicmonocarboxylic acids, the saturated alkanoic dicarboxylic acids, and thehydroxyalkanoic acids (e.g. tartaric acid), are used as furtheradditives. The number of C atoms in these carboxylic acids is may bewithin the range of 2 to 20. The addition of organic acids, such ascarboxylic acids, leads to an increase in wet adhesion and to aprolongation of the duration of adhesion, brought about by interactionsbetween acids and cellulose derivatives, especially sodium carboxymethylcellulose, e.g. by partial esterification.

The total portion of polymers in the adhesives according to theinvention, or in the adhesive layers produced therefrom, amounts to45-99%-wt., relative to the adhesive compound or the adhesive layer; theremainder consists of auxiliary substance(s) or additive(s) and/oractive substance(s), as well as optionally a solvent portion. Suitableas solvents for the inventive adhesive compositions are water, aqueoussolvent mixtures, alcohols, esters (such as ethyl acetate, for example)and other polar solvents.

Particularly advantageous are in addition those adhesive formulationsaccording to the invention which in addition to the moisture-activatableadhesive formulation contain one or more pressure-sensitive adhesivepolymers. Such adhesives and the adhesive layers obtained therefromthereby possess both the advantages of conventional pressure-sensitiveadhesives and the advantages which are brought about by themoisture-activatable adhesive compositions according to the invention.The inventive adhesives which additionally contain pressure-sensitiveadhesive polymers particularly stand out by the fact that their adhesivepower is activated and/or even increased upon action of moisture. At thesame time they also possess sufficient adhesive power when no skinmoisture is present.

The pressure-sensitive adhesive polymers selected may be those from thegroup of the polyacrylates, polyisobutylenes and polyisoprenes, siliconadhesives and hot melt pressure-sensitive adhesives. Polyacrylates areunderstood to be polymers based on acrylic acid or methacrylic acid andtheir esters, as well as mixtures of such polymers. Suitablepolyacrylates are known to the skilled artisan (cf. Example 3).

The portion of moisture-activatable or non-pressure-sensitive adhesivecomponents (components (a) to (e)) here may be 40 to 60%-wt.

The moisture-activatable adhesive formulations according to theinvention can be used to advantage to produce medical patches ortransdermal therapeutic systems (TTSs). Such patches and systemscomprise at least one moisture-activatable adhesive matrix layer made ofan adhesive according to the invention or containing such adhesive;mixtures of such adhesives may likewise be used. The structure of suchpatches or TTSs is in principle known to those skilled in the art; apartfrom the mentioned adhesive layer(s), it comprises a carrier or backinglayer (e.g. a plastics film such as PET film, or a textile material) towhich the adhesive layer is applied. That side of the adhesive layerwhich adheres to the skin is usually covered with an adhesively coatedprotective film; this can, however, also be dispensed with, as mentionedhereinabove.

In principle, the moisture-activatable systems according to theinvention can be used in all cases where a flat-shaped object has to beattached to a support, especially a moist support, for a certain periodof time.

In the case of TTSs, the matrix layer, made of one (or more)moisture-activatable pressure-sensitive adhesive formulation(s)according to the invention, contains at least one active substance. Thisactive substance may be present in the matrix layer in dissolved ordispersed form, in the form of an emulsion or in solid form. Activesubstances are understood to be, in principle, any substances, substancemixtures or preparations which are suitable for topical or transdermaladministration and which can have a physiological effect in the human oranimal body, especially medicinal active substances, hormones, traceelements, enzymes and antigens. The active substances may serve to carryout therapeutic, prophylactic or cosmetic treatment.

Particularly, the following active substances and active substancegroups are suitable:

-   -   1. Salts of basic or acidic active substances from the group of        the ACE inhibitors, anabolics, antidiabetics, antihypertonics,        anti-infectives, anticoagulants, antirheumatics, diuretics,        hormones, immunosuppressants, laxatives, lipid-lowering agents,        CNS-active compounds, anti-epileptics, antihypertonics, coronary        therapeutic agents, etc.;    -   2. substances whose activity is increased by admission of water,        which leads to higher active substance flux rates;    -   3. hydrophile active substances which are hardly soluble in        hydrophobic polymers, e.g. insulin, erythropoietin, growth        factors, gonadoliberins, oxytocin, prolactin, calcitonin,        parathyrin (parathormone), somatomedin, melanotropin.

According to an additional embodiment of the present invention, themoisture-activatable adhesive matrix of a medical patch, butparticularly of a TTS, is connected with an overlying patch. The area ofthe latter is larger than that of the moisture-activatable adhesivematrix; namely, the overlying patch projects beyond the surface of thematrix layer at all sides thereof. It is furthermore advantageous toalso provide the overlying patch with a pressure-sensitive adhesivepolymer layer on the skin-facing side.

In the following, the invention will be illustrated by means of examplesof formulations.

EXAMPLE 1

Moisture-activatable adhesive without addition of pressure-sensitiveadhesive

Constituent Component amount MOWIOL ® 28-99  9.1%-wt. Gantrez AN-13990.9%-wt. Water

MOWIOL® 28-99: polyvinyl alcohol (by Hoechst/Aventis)

Gantrez AN-139: polymethyl vinyl ether-polymaleic acid anhydridecopolymer (by ISP)

Process of manufacture: Demineralised water is placed in a suitablemixing vessel, and MOWIOL® 29-99 (polyvinyl alcohol) is introduced whilestirring and dissolved completely at 80 to 90° C. Gantrez AN-139(polymethyl vinyl ether polymaleic acid anhydride copolymer) is strewninto the solution, and this is likewise stirred under the influence oftemperature (80-90° C.), until a homogenous mass is obtained.

EXAMPLE 2

Moisture-activatable adhesive with film-forming polyacrylate

Constituent Component amount EUDRAGIT ® NE 40 D 71.0%-wt. Gantrez AN-16928.6%-wt. Sorbitol  0.4%-wt. Ethanol

EUDRAGIT® NE 40 D: non-pressure-sensitive adhesive, film-formingpolyacrylate (by Röhm)

Gantrez AN-169: see Example 1.

Preparation: Ethanol is placed in a suitable mixing vessel, and sorbitolis strewn in while stirring and homogenising. EUDRAGIT® NE 40 D andGantrez AN-169 are introduced while stirring, the mixture is stirred atapprox. 50-70° C. until a homogenous mass is obtained.

EXAMPLE 3

Moisture-activatable adhesive with addition of pressure-sensitiveadhesive

Constituent Component amount Gantrez S-97 BF 50.0%-wt. DURO-TAK ®326-2353 50.0%-wt. Hexane Ethyl acetate Ethanol

DURO-TAK®326-2353: Polyacrylate pressure-sensitive adhesive (by NationalStarch & Chemical B.V.)

Gantrez S-97 BF: Acid form of a Gantrez AN polymer.

Manufacturing process: Ethanol is placed into a suitable mixing vessel,and Gantrez S-97 BF is introduced while stirring. This is stirred untila homogenous mass is obtained. Thereafter, the DURO-TAK® adhesivecompound is stirred in.

The compounds prepared according to the above examples are coated,employing an Erichsen doctor knife, a spread coating box or a coatingmechanism, on a suitable processing film and subsequently dried in thedrying cabinet or the drying tunnel.

The adhesive films prepared according to Examples 1 and 2 are notself-adhesive, rather their tackiness is activated only by moisteningthe area provided for adhering or after moistening the polymer matrix,as well as upon contact with a moist substrate. The adhesive filmsproduced according to Example 3 are already adhesive in dry state due tothe addition of pressure-sensitive adhesive (DURO-TAK®). In preliminarytests, periods of adhesion to the skin in the range of 12 to 24 h wereachieved with the exemplary formulations 1 and 2. After removing theactive substance patches, which contained an adhesive film according tothe above examples, from the skin no residues remained on the skin, oralternatively the residues could easily be washed off with water.

By means of the modifications described in the subclaims, it is possibleto further optimize the adhesive effect.

What has been described above are preferred aspects of the presentinvention. It is of course not possible to describe every conceivablecombination of components or methodologies for purposes of describingthe present invention, but one of ordinary skill in the art willrecognize that many further combinations and permutations of the presentinvention are possible. Accordingly, the present invention is intendedto embrace all such alterations, combinations, modifications, andvariations that fall within the spirit and scope of the appended claims.

1. An adhesive composition for preparing an adhesive layer for medicalpatches or for transdermal therapeutic systems, said adhesive layerhaving a tackiness which is activated and/or increased by contact withmoisture or by absorption of moisture, wherein said adhesive layercomprises at least one pressure-sensitive adhesive polymer and at leastone component selected from the group consisting of polyethers and acidanhydrides including acids and salts of acid anhydrides, saidcomposition comprising: polyvinylalcohol and at least one polymethylvinyl ether-polymaleic acid anhydride copolymer, wherein the portion ofpolyvinylalcohol is 1-80%-wt, relative to the sum of said two polymers;at least one film-forming polymer being at least one selected from thegroup consisting of non-pressure-sensitive adhesive polyacrylates and atleast one pressure-sensitive adhesive polymer; and a solvent portionincluding a solvent.
 2. The adhesive composition according to claim 1,wherein the solvent of said solvent portion is a polar solvent.
 3. Theadhesive composition according to claim 1, wherein the solvent of saidsolvent portion is selected from the group consisting of water, aqueoussolvent mixtures, alcohols and esters.
 4. The adhesive compositionaccording to claim 1, wherein the solvent of said solvent portioncomprises hexane and ethyl acetate.
 5. The adhesive compositionaccording to claim 1, wherein said at least one pressure-sensitiveadhesive polymer is selected from the group consisting of polyacrylates,polyisobutylenes, polyisoprenes and silicone adhesives.
 6. The adhesivecomposition according to claim 1, wherein said composition furthercomprises at least one component selected from the group consisting ofcellulose derivatives and polyethers.
 7. The adhesive compositionaccording to claim 6, wherein said at least one cellulose derivative isselected from the group consisting of hydroxypropyl methyl cellulose,hydroxypropyl cellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose and hydroxypropyl ethyl cellulose. 8.The adhesive composition according to claim 6, wherein said polyethersare polyvinylalkyl ethers selected from the group consisting ofpolyvinyl methyl ether, polyvinyl ethyl ether, polyvinyl isobutyl etherand polyvinyl cyclohexyl ether.